Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi synthetic and totally synthetic analogs thereof.
The naturally occurring compounds and their semi-synthetic analogs have the following general structural formulae: ##STR2## wherein:
R.sup.3 is hydrogen, C.sub.1-5 or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R.sup.* is ##STR3## wherein Q is ##STR4## or R.sup.5 --CH; R.sup.5 is H or OH; M is --CHR.sup.6, R.sup.6 is hydrogen or hydroxy;
R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR5## or ##STR6## and when d is a double bond, M is ##STR7##
U.K. Patent 2,075,013 discloses semi synthetic hydroxy containing compounds represented by the above general formula wherein R.sup.* ##STR8## wherein R.sup.1 is H or Me, and R.sup.2 is H or acyl.
U.S. Patent Application Serial No. 048,136 filed May 15, 1987 discloses 6-substituted compounds of the above general formula wherein R.sup.* is: ##STR9## wherein R is Ch.sub.2 OH, ##STR10## CO.sub.2 R.sup.7 or ##STR11## and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. Pat. Nos. 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R.sup.* is: ##STR12## wherein X represents a hydrogen atom or a
2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 where R.sup.3 is a hydrogen or alkyl moiety.
Copending U.S. patent applications Ser. Nos. 213,010 filed June 29 1988, 322,398 filed Mar. 13, 1989 and now U.S. Pat. No. 4,463,538 and Ser. No. 250,646 filed Sept. 29, 1988 and now U.S. Pat. No. 4,921,924 disclose compounds of the above general formula wherein R.sup.* is: ##STR13## wherein R.sup.5 and R.sup.6 are H, OH, OR.sup.7 or together represent C=0. These applications disclose a scheme for preparing a 5-oxo compound which involves treatment of an alkene with NBS to form a bromohydrin and oxidation of the hydroxy moiety of the bromohydrin with pyridinium chlorochromate followed by displacement of the bromine. The disclosed process presents problems of relatively low yield and the employment of environmentally undesirable substances, particularly in the transformation to large scale reactions.